First-ever Lacunar Stroke Patients Research Articles

Plasma tPA-Activity and Progression of Cerebral White Matter Hyperintensities in Lacunar Stroke Patients.

IntroductionTissue plasminogen activator (tPA)-activity and plasminogen activator inhibitor type 1 (PAI-1) antigen are considered to be haemostasis-related markers of endothelial activation and relate to presence of cerebral white matter hyperintensities (WMH) as was earlier shown in a cross-sectional study. We investigated whether tPA-activity and PAI-1 levels are associated with WMH progression in a longitudinal study.MethodsIn 127 first-ever lacunar stroke patients in whom baseline brain MRI and plasma levels of tPA-activity and PAI-1-antigen were available, we obtained a 2-year follow-up MRI. We assessed WMH progression by a visual WMH change scale. We determined the relationship between levels of tPA-activity and PAI-1 and WMH progression, by logistic regression analysis.ResultsPlasma tPA-activity was associated with periventricular WMH progression (OR 2.36, 95% CI 1.01–5.49, with correction for age and sex and baseline presence of WMH), but not with deep or any (periventricular and/or deep) WMH progression. PAI-1 levels were lower in patients with WMH progression, but these results were not significant.ConclusionWe found a relationship between plasma tPA-activity and progression of periventricular WMH. More research is needed to determine whether there is a (direct) role of tPA in the development and progression of WMH.

Dilated Virchow–Robin Spaces in First-Ever Lacunar Stroke Patients: Topography and Clinical Correlations

Dilated Virchow-Robin spaces (dVRSs) were regarded as a phenotype of cerebral small-vessel disease (SVD). However, the clinical correlations of dVRS were still unclear. In this study, we aimed to investigate the topography and clinical correlations of dVRS in first-ever lacunar stroke patients. Patients with first-ever lacunar stroke were recruited and had magnetic resonance scans to identify the presence and degree of dVRS in the basal ganglia (BG-dVRS), dVRS in the central semiovale (CSO-dVRS), leukoaraiosis, and silent brain infarction (SBI). The neurological deficits after stroke onset and functional outcome after 1 year were evaluated using National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale, respectively. Clinical and radiological features were compared between patients with high and low degrees of dVRS, and between patients with favorable and unfavorable outcomes. Logistic regression models were constructed to identify the risk factors of unfavorable outcome. The NIHSS scores were not statistically different between patients with high and low degrees of dVRS. More patients with high degrees of BG-dVRS had unfavorable outcomes than those with low degrees of BG-dVRS. Logistic regression showed that the degrees of BG-dVRS, leukoaraiosis, and SBIs were not independent risk factors for the unfavorable outcome, whereas the total burden of SVD was an independent risk factor for the unfavorable outcome. The degrees of either BG-dVRS or CSO-dVRS were not associated with the severity of first lacunar stroke. BG-dVRS was related to the unfavorable 1-year outcome. This association might be based on the total severity of SVD.

Factors Associated with Severity of Leukoaraiosis in First-ever Lacunar Stroke and Atherosclerotic Ischemic Stroke Patients

Leukoaraiosis (LA) is an indicator of small vessel disease, but little is known about the relationship between the severity of LA and etiologic subtype of ischemic stroke. Our study aimed to investigate the factors associated with the severity of LA and the relationship between the severity of LA and etiologic subtype of ischemic stroke. A total of 791 patients with first-ever ischemic stroke within 7 days were enrolled in our study. We evaluated cranial magnetic resonance imagings including severity of LA in periventricular and deep white matter, severity of silent lacunar infarcts (SLIs), etiologic subtype of ischemic stroke, and topographic patterns of acute cerebral infarcts. Severity of LA was graded as grade 0 when Fazekas scores = 0, grade 1 when Fazekas scores ranged from 1 to 2, and grade 2 when Fazekas scores were greater than or equal to 3. Multivariable ordinal logistic regression was used to analyze the factors associated with the severity of LA. A total of 748 patients (94.6%) had LA, the numbers and proportions of grade 0, grade 1, and grade 2 LA were 43 patients (5.4%), 413 patients (52.2%), and 335 patients (42.4%), respectively. In multivariable ordinal logistic regression analysis, increasing age, higher diastolic blood pressure, admission National Institutes of Health Stroke Scale scores less than or equal to 3, presence of SLIs, and small artery occlusion (SAO) subtype of ischemic stroke were found to be independently associated with higher grade of LA. LA is prevalent in first-ever ischemic stroke patients. Severe LA is more frequently associated with higher grades of SLIs and ischemic stroke due to SAO.

Abstract W P371: Cerebral Microbleeds and Renal Impariment in Acute Lacunar Stroke

Background and purpose: Cerebral small vessel disease is associated with chronic kidney disease. Although cerebral microbleeds (CMB) are common in patients with lacunar stroke, the association between CMB and renal impairment remains unclear. The aim of this study was to clarify whether CMB are associated with renal impairment in patients with acute lacunar stroke. Methods: We evaluated consecutive first-ever lacunar stroke patients who were admitted to our hospital within 24 hours after stroke onset. Lacunar infarcts were defined as <15 mm in diameter detected on initial diffusion-weighted imaging scans and depended on the criteria for small artery occlusion based on the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. CMB were defined as a focal area of signal loss in brain parenchyma <5 mm on T2*-weighted imaging scans. We divided patients into two groups according to the presence or absence of CMB. Results: Among 152 patients (66% male, mean age 69 years), 45 (30%) had CMB. The presence of silent lacunar infarcts (SLI; 87% vs 41%, P <0.001), white matter disease (WMD; 67% vs 26%, P <0.001), and hypertension (84% vs 66%, P <0.05) were higher and estimated glomerular filtration rate (eGFR) on admission (67.7 vs 79.0 mL/min/1.73 m 2 , P <0.01) was lower in patients with CMB than in those without. The frequency of CMB showed a significant difference among tertiles of eGFR (highest, middle, and lowest; 14%, 35%, and 40%, P <0.01). On multivariable logistic regression analysis, SLI (odds ratio, 95% confidence interval; 11.1, 3.8-37.7), hypertension (5.1, 1.6-18.9), WMD (4.6, 1.6-13.8), eGFR on admission (lowest and middle tertiles vs highest tertile, 3.3, 1.1-10.9), NIHSS score on admission (1.3, 1.0-1.6), and diabetes mellitus (0.1, 0.04-0.41) were independently associated with CMB. Conclusions: In lacunar stroke patients, the presence of CMB should be associated with renal impairment.

Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study

BackgroundThe detection of early neuropsychological abnormalities as precursors of cognitive decline of vascular origin in patients with lacunar stroke is a subject of increasing interest. The objective of this study was to assess whether there were differences in the performance of a battery of neuropsychological tests in first-ever lacunar stroke patients with and without associated silent multiple lacunar infarctions found incidentally on the brain magnetic resonance imaging (MRI) scan.MethodsA total of 72 consecutive patients with first-ever lacunar infarction were studied 1 month after stroke. All patients underwent a comprehensive neuropsychological evaluation, which included the California Verbal Learning Test (CVLT), Phonetic Verbal Fluency Test (PMR), Semantic Verbal Fluency Test (category “animals”), Digit Span Forward and Backward from the Wechsler Adult Intelligence Scale (WAIS-III), and Mini-Mental State Examination (MMSE).ResultsA total of 38 patients (52.7%) had silent multiple lacunar infarcts, with corona radiata as the most frequent topography (P < 0.023). White matter hyperintensities (leukoaraiosis) were observed in 81.1% of patients with silent multiple lacunar infarcts and in 50% with a single lacunar infarction (P < 0.007). Patients in both groups showed similar scores in the MMSE, but those with associated silent lacunar infarctions showed a poorer performance in the semantic fluency test (P < 0.008) and in short delayed verbal memory (P < 0.001). In both cases, however, leukoaraiosis was not statistically significant in multivariate linear regression models adjusted by confounding covariates. In these models, multiple silent lacunar infarctions and education were independent predictors of poor performance in the semantic fluency test and in short delayed verbal memory.ConclusionsThe presence of silent multiple lacunar infarctions documented on brain MRI scans in patients with first-ever lacunar stroke was associated with mild neuropsychological abnormalities, particularly in the performance of executive functions (semantic fluency) and short delayed verbal memory. According to these findings, in the initial stages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunes rather than to leukoaraiosis or perivascular hyperintensities of vascular cause.

Vitamin B12 and Progression of White Matter Lesions. A 2-Year Follow-Up Study in First-Ever Lacunar Stroke Patients

In cross-sectional studies periventricular white matter lesions (WML) were related to low plasma levels of vitamin B12. Whether low vitamin B12 levels are also related to progression of WML is still unknown. We studied baseline vitamin B12 levels and its association with progression of WML over 2 years of follow-up in first-ever lacunar stroke patients. In 107 first-ever lacunar stroke patients in whom baseline brain MRI and vitamin B12 status were available, we obtained a follow-up brain MRI after 2 years. We assessed progression of periventricular WML (pWML) and deep WML (dWML) using a visual WML change scale. We studied the relationship between baseline levels of plasma vitamin B12 and progression of WML after 2 years of follow-up by binary logistic regression analyses. Vitamin B12 deficiency was more frequent in patients with progression of pWML compared to those without progression (41.9% and 19.7% respectively, p = 0.02). Corrected for sex and age, progression of pWML was associated with lower baseline levels of vitamin B12 (OR 1.42 per 50 unit decrease, 95% CI 1.00-1.92). Vitamin B12 levels were not associated with progression of dWML. In conclusion progression of pWML after 2 years of follow-up relates to low levels of vitamin B12 at baseline in first-ever lacunar stroke patients. Whether this population could benefit from vitamin B12 supplementation is unknown and requires further investigation.

Higher Ambulatory Blood Pressure Relates to New Cerebral Microbleeds

Elevated blood pressure (BP) is associated with the presence of cerebral microbleeds (CMBs) in cross-sectional studies. However, longitudinal studies did not show a convincing relationship. We aimed to determine the association between elevated BP levels and the occurrence of new CMBs after a 2-year follow-up in first-ever lacunar stroke patients using ambulatory BP monitoring. Ninety-six first-ever lacunar stroke patients underwent brain MRI and ambulatory BP monitoring at baseline and after 2-year follow-up. We used logistic regression analyses to assess the association of BP levels with new CMBs. We found new CMBs in 17 patients (18%). Higher 24-hour, day and night systolic BP (odds ratio, 2.69; 95% confidence interval, 1.40-5.21 per SD increase for 24-hour BP) and diastolic BP (odds ratio, 2.13; 95% confidence interval, 1.15-3.90 per SD increase for 24-hour BP) at baseline were associated with the development of new CMBs independent of age and sex. BP levels decreased during follow-up in both patients with and without new CMBs. Unlike BP levels at baseline, there was no difference in BP levels at follow-up between patients with and without new CMBs. Both higher systolic and diastolic BP levels were associated with the development of new CMBs in a population of lacunar stroke patients. Decrease of BP levels during follow-up did not halt progression of CMBs; however, it remains to be determined whether (early) intervention with antihypertensive drugs can slow down progression of CMBs.

Accumulation of MRI Markers of Cerebral Small Vessel Disease is Associated with Decreased Cognitive Function. A Study in First-Ever Lacunar Stroke and Hypertensive Patients

Background: White matter lesions (WMLs), asymptomatic lacunar infarcts, brain microbleeds (BMBs), and enlarged perivascular spaces (EPVS) have been identified as silent lesions due to cerebral small vessel disease (cSVD). All these markers have been individually linked to cognitive functioning, but are also strongly correlated with each other. The combined effect of these markers on cognitive function has never been studied and would possibly provide more useful information on the effect on cognitive function.Methods: Brain MRI and extensive neuropsychological assessment were performed in 189 patients at risk for cSVD (112 hypertensive patients and 77 first-ever lacunar stroke patients). We rated the presence of any asymptomatic lacunar infarct, extensive WMLs, any deep BMB, and moderate to extensive EPVS in the basal ganglia. The presence of each marker was summed to an ordinal score between 0 and 4. Associations with domains of cognitive function (memory, executive function, information processing speed, and overall cognition) were analyzed with correlation analyses.Results: Correlation analyses revealed significant associations between accumulating cSVD burden and decreased performance on all cognitive domains (all p ≤ 0.001). Results remained significant for information processing speed (r = −0.181, p = 0.013) and overall cognition (r = −0.178, p = 0.017), after correction for age and sex. Testing of trend using linear regression analyses revealed the same results.Discussion: We tested a new approach to capture total brain damage resulting from cSVD and found that accumulation of MRI burden of cSVD is associated with decreased performance on tests of information processing speed and overall cognition, implying that accumulating brain damage is accompanied by worse cognitive functioning.

The Appearance of a New White Matter Lesion Adjacent to the Old Infarct in First-Ever Lacunar Stroke Patients: A Two-Year Follow-Up Study with MRI

The Appearance of a New White Matter Lesion Adjacent to the Old Infarct in First-Ever Lacunar Stroke Patients: A Two-Year Follow-Up Study with MRI

Higher ambulatory blood pressure relates to enlarged Virchow-Robin spaces in first-ever lacunar stroke patients

Enlarged Virchow-Robin spaces (EVRS) are considered to be a sign of cerebral small vessel disease. Hypertension is an important risk factor for cerebral small vessel disease, whereas ambulatory blood pressure (BP) is the strongest predictor of hypertension-related brain damage. However, the association between ambulatory BP levels and EVRS has never been investigated. The aim of this study was to determine the association between ambulatory BP levels and EVRS. In 143 first-ever lacunar stroke patients, we performed 24-h ambulatory BP monitoring after the acute stroke phase. On brain MRI we counted EVRS in the basal ganglia and the centrum semiovale. We graded the number of EVRS at each level into a three-category severity scale. We assessed the association between BP levels and EVRS by ordinal regression analysis. After adjusting for age, sex, extensive white matter lesions, and asymptomatic lacunar infarcts, higher day systolic (OR 1.21; 95 % CI 1.00–1.46 per 10 mmHg), day diastolic (1.18; 95 % CI 1.02–1.37 per 5 mmHg) and 24-h diastolic (OR 1.18; 95 % CI 1.01–1.37 per 5 mmHg) ambulatory BP levels were associated with EVRS at the basal ganglia level. No relation was found between ambulatory BP levels and EVRS in the centrum semiovale. Higher day ambulatory BP levels are associated with EVRS in the basal ganglia. This association was independent of the presence of extensive white matter lesions and asymptomatic lacunar infarcts. Our results imply that basal ganglia EVRS should be regarded as a separate manifestation of BP-related brain damage.

Levels of heparin-releasable TFPI are increased in first-ever lacunar stroke patients

New insights in the pathophysiology of lacunar stroke (LS) suggest that it is caused by increased permeability of the blood-brain barrier due to endothelial activation. Because endothelial cells are the major production and storage site of tissue factor pathway inhibitor (TFPI), this protein can be used as marker of endothelial activation. In this observational study we measured the different pools of TFPI, as a marker of endothelial function, in first-ever lacunar stroke patients. We determined antigen levels of total and free full-length (FL) TFPI using ELISA in 149 patients and 42 controls. Heparin-releasable free FL TFPI was determined in a random subset of 17 patients and 15 controls. By brain MRI, we classified LS patients as having isolated lacunar infarct (ILA) or silent ischemic lesions (SILs). Plasma levels of total TFPI were highest in patients with SILs compared with those with ILA, but this association disappeared after correction for age and levels of low-density lipoprotein cholesterol. However, levels of heparin-releasable free FL TFPI were higher in patients than in controls. Although ambient plasma levels of total TFPI were not different in subtypes of LS, the increased levels of heparin-releasable TFPI in patients suggest a role of endothelial activation in the pathogenesis of LS.

Association of Vitamin B12 Deficiency with Fatigue and Depression after Lacunar Stroke

BackgroundIn lacunar stroke patients vitamin B12 deficiency is often found and a relationship with the degree of periventricular white matter lesions (pWMLs) is suggested. Given the known relationships between WMLs and depression and between depression and fatigue after stroke, we studied both depression and fatigue in lacunar stroke patients with and without vitamin B12 deficiency.MethodsIn 40 first-ever lacunar stroke patients vitamin B12 levels were determined and self-report questionnaires for fatigue and depression were completed three months after stroke.ResultsLacunar stroke patients with vitamin B12 deficiency (N = 13) reported significantly more fatigue (90.7 versus 59.4; p = .001) and depressive symptoms (6.62 versus 3.89; p<.05) than those without (N = 27). In regression analyses, vitamin B12 deficiency was significantly and independently associated with the presence of severe fatigue and clinically significant depression.ConclusionsOur preliminary results suggest a relationship between vitamin B12 deficiency and increased levels of fatigue and depression in lacunar stroke patients. If these findings could be replicated in a larger and general stroke sample, this would open treatment options and may improve quality of life after stroke.

Estimating the Magnitude of Genetic Factors by Calculating the Genetic Relative Risk of Stroke in First-Ever Lacunar Stroke Patients

BackgroundPositive family history of stroke is an independent risk factor for lacunar stroke. However, the magnitude of familial aggregation of a certain disease is better evaluated by the genetic relative risk. This is calculated by dividing the prevalence of specific disease in family members of patients by the prevalence of this disease in the general population. In a cohort of lacunar stroke patients, who were subtyped clinically and radiologically, we determined the genetic relative risk of stroke.MethodsBy questionnaire and additional interview, we obtained a complete first-degree family history of stroke. The prevalence of stroke in first-degree relatives of these lacunar stroke patients was compared to the self-reported prevalence of stroke in a Dutch community based cohort of elderly volunteers. Secondly, the influence of proband characteristics and family composition on parental and sibling history of stroke were evaluated.Principal FindingsWe collected data of 1066 first-degree relatives of 195 lacunar stroke patients. Strokes occurred in 13.5% of first-degree relatives. The genetic relative risk was 2.94 (95%CI 2.45–3.53) for overall first-degree relatives, 4.52 (95%CI 3.61–5.65) for patients' parents and 2.10 (95%CI 1.63–2.69) for patients' siblings. Age of proband and proband status for hypertension influenced the chance of having a parent with a history of stroke whereas the likelihood of having a concordant sibling increased with sibship size.ConclusionsWe found an increased genetic relative risk of stroke in first-degree relatives of patients with lacunar stroke. Our data warrant further genomic research in this well-defined high risk population for stroke.

Vascular inflammation in cerebral small vessel disease

Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD.

Response to Letter Regarding Article “Endothelial Activation in Lacunar Stroke Subtypes”

Response: We thank Dr Tsuda for his comments on our article in the August 2010 issue of Stroke regarding the hemostasis-related endothelial markers in first-ever lacunar stroke patients.1 First, Dr Tsuda points to the relation between the endogenous nitric oxide inhibitor asymmetrical dimethylarginine and cerebral small vessel disease, in particular in relation with ischemic white matter lesions.2 In our study, we evaluated endothelial function by measuring levels of hemostasis-related proteins normally excreted by the endothelium, and …

Brain Microbleeds Relate to Higher Ambulatory Blood Pressure Levels in First-Ever Lacunar Stroke Patients

Hypertension is an important risk factor for brain microbleeds (BMBs) in lacunar stroke patients. However, beyond the qualitative label "hypertension," little is known about the association with ambulatory blood pressure (BP) levels. In 123 first-ever lacunar stroke patients we performed 24-hour ambulatory BP monitoring after the acute stroke-phase. We counted BMBs on T2*-weighted gradient-echo MR images. Because a different etiology for BMBs according to location has been suggested, we distinguished between BMBs in deep and lobar location. BMBs were seen in 36 (29.3%) patients. After adjusting for age, sex, number of antihypertensive drugs, asymptomatic lacunar infarcts, and white matter lesions, we found 24-hour, day, and night systolic and diastolic BP levels to be significantly associated with the presence and number of BMBs (odds ratios 1.6 to 2.3 per standard deviation increase in BP). Distinguishing between different locations, various BP characteristics were significantly associated with the presence of deep (or combined deep and lobar) BMBs, but not with purely lobar BMBs. Our results underline the role of a high 24-hour BP load as an important risk factor for BMBs. The association of BP levels with deep but not purely lobar BMBs is in line with the idea that different vasculopathies might be involved. Deep BMBs may be a particular marker of BP-related small vessel disease, but longitudinal and larger studies are now warranted to substantiate these findings.

A SELDI-TOF-MS Study in Lacunar Stroke with Subsequent Haptoglobin Phenotyping

Using Surface-Enhanced Laser Desorption / Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS), we aimed to detect differences in protein profile in serum samples of two lacunar stroke subtypes. SELDI-TOF-MS, followed by protein identification, was performed in samples of 8 first-ever lacunar stroke patients with MR imaging showing a single symptomatic lacunar lesion (type 1), and 8 with multiple additional "silent" lacunar lesions and extensive white matter lesions (type 2). A 16 kDa protein, identified as alpha-2-chain of haptoglobin (Hp), was found to be overrepresented in type 1 compared to type 2 (peak intensity 12.5 vs. 5.0; p=0.02). As a polymorphism with two alleles, Hp-1 and Hp 2, determines the presence of alpha-1 and/or alpha-2-chains in the Hp-molecule, Hp phenotypic analysis was performed. Hp 1 : Hp-2 allele frequency was 0.562 : 0.438 in type 1 and 0.812 : 0.188 in type 2 (population reference approximately 0.4 : 0.6). We conclude that the overrepresentation of the alpha-2-chain in lacunar stroke type 1 compared to type 2 relates to a higher Hp-2 allele frequency in the former. Yet, compared to population reference, the phenotype distribution in both patient groups deviates towards a high Hp-1 allele frequency. Our findings suggest a role for the Hp gene in the etiology of cerebral small vessel disease. Larger studies are now needed to explore this new candidate gene.